Pharmaceutical Compositions

ABSTRACT

The present Invention relates to pharmaceutical compositions of (3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide, useful in the treatment or prevention of Human Immunodeficiency Virus (HIV) infections.

BACKGROUND OF THE INVENTION

WO 2006/116764 discloses a class of compounds useful in the treatment ofHIV infection and AIDS. There is a continuing need for pharmaceuticalcompositions suitable for treatment over a long period of time. We havediscovered pharmaceutical compositions of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidethat are long-acting and therefore suitable for administration topatients in the treatment of HIV infections.

Patient non-compliance is a well known problem accompanying the complexHIV treatment regimens. Patient non-compliance is a critical problem inthe treatment of HIV because such non-compliance may lead to theemergence of multiple-drug resistant strains of HIV.

The present invention addresses the issue of non-compliance byformulating(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamideas a long-acting parenteral composition suitable for administration, forexample, once per month, once every 2 months, once every 3 months, onceevery 6 months or once every 12 months.

The compositions of the present invention provide for once monthlydosing or longer, thereby addressing the problem of patientnon-compliance and pill burden.

SUMMARY OF THE INVENTION

The present Invention relates to pharmaceutical compositions of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamideuseful in the treatment or prevention of Human Immunodeficiency Virus(HIV) infections.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Plasma Concentration-Time Profiles of a Compound of Formula (I)in Individual Male or Female Rats Following a Single SubcutaneousInjection of a compound of formula (I) Followed by at least a 74-DayNontreatment Period at a Nominal Dose of 5, 30, or 100 mg/kg.

FIG. 2: Plasma Concentration-Time Profiles of a Compound of Formula (I)in Individual Female Rats Following a Single Subcutaneous Injection of acompound of formula (I) Followed by at least a 74-Day NontreatmentPeriod at a Nominal Dose of 5, 30, or 100 mg/kg.

FIG. 3: Plasma Concentration-Time Profiles of a Compound of Formula (I)in Individual Male or Female Rats Following a Single IntramuscularInjection of a compound of formula (I) Followed by at least a 74-DayNontreatment Period at a Nominal Dose of 2.5, 10, or 75 mg/kg.

FIG. 4: Plasma Concentration-Time Profiles of a Compound of Formula (I)in individual Female Rats Following a Single Intramuscular Injection ofa compound of formula (I) Followed by at least a 74-Day NontreatmentPeriod at a Nominal Dose of 2.5, 10, or 75 mg/kg.

DETAILED DESCRIPTION OF THE INVENTION

(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide,a compound of formula (I), also referred to as compound (I), has provenantiviral activity against human immunodeficiency virus (HIV).

The present invention features pharmaceutical compositions comprisingthe active ingredient(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide,or a pharmaceutically acceptable salt thereof, suitable foradministration once monthly or longer.

A further feature of the present invention is a method of using thesepharmaceutical compositions.

The present invention features pharmaceutical compositions, comprising(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide,or a pharmaceutically acceptable salt thereof, and a surfactant system.

The present invention features a pharmaceutical composition, comprisinga therapeutically effective amount of(3S,11aR)-N-[(2,4-difluorophenyl)methyl]-2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-dioxo-oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide,or a pharmaceutically acceptable salt thereof, and a surfactant system.

Pharmaceutically acceptable salts include, but are not limited tocalcium, magnesium, sodium, or potassium salts and solvates such ashydrates or alcoholates.

The term “therapeutically effective amount,” as used herein, means asufficient amount of a drug, compound, composition, product orpharmaceutical agent to abate or reverse or treat a malady in a human orother mammal.

The present invention features parenteral pharmaceutical compositionsfor administration to a subject, for example a human.

The present invention features long-acting parenteral pharmaceuticalcompositions comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a surfactant system for once monthlyadministration.

The present invention features long-acting parenteral pharmaceuticalcompositions comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a surfactant system for bi-monthly (onceevery two months) administration.

The present invention features long-acting parenteral pharmaceuticalcompositions comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a surfactant system for tri-monthly (onceevery three months) administration.

The present invention features long-acting parenteral pharmaceuticalcompositions comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a surfactant system administration onceevery six or twelve months, or any time point within this range.

The compositions of the present invention provide for the slow releaseof a compound of formula (I). Therefore, in order to achieve therapeuticlevels of drug, a compound of formula (I) advantageously is releasedfrom the composition within approximately one to three months, or anytime point within this range.

An embodiment of the present invention is a pharmaceutical compositionsuitable for parenteral administration comprising a compound of formula(I) and a surfactant system comprising a combination of polymersproviding for the release of a compound of formula (I) over a period ofone to three months. A suitable combination of polymers is, for example,polysorbate 20 and polyethylene glycol (PEG) 3350.

A suitable combination of polymers, namely wetting agent and stabilizer,is required to manufacture a stable suspension. Wetting agents can beselected from a class of non-ionic and anionic surfactants.Representative examples of wetting agents include polyoxyethylene castoroil derivatives, polyoxyethylene sorbitan fatty acid esters(Polysorbate), sorbitan esters of fatty acids (SPAN), Poloxamers, suchas LUTROL™ F68, F108 and F127 which are block copolymers of ethyleneoxide and propylene oxide, sodium dodecylsulfate and sodium laurylsulphate.

Representative stabilizers include, but are not limited to, polyethyleneglycols, carboxymethylcellulose calcium, carboxymethylcellulose sodium,methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxymethylpropylcellulose, polysaccharides, hyaluronic acid,polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP).

An example of combination of polymers includes a polysorbate, forexample, polysorbate 20 or polysorbate 60 as wetting agent and apolyethylene glycol (PEG), for example, PEG 3350, PEG4000 or PEG8000 asstabilizer.

The present invention features a parenteral pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, and polysorbate 20 and polyethylene glycol (PEG) 3350.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system that may be nanomilled to 200 nM.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system that may be nanomilled to 200 nM in less than 10 hourson a ball mill.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system that may be size reduced to a mean particle size of0.1-1.0 μm.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system that may be size reduced to a mean particle size of0.1-0.5 μm or 0.2-0.4 μm.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system that may be size reduced to a mean particle size of0.1-1.0 μm using wet bead milling.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system that may be size reduced to a mean particle size of0.1-1.0 μm using a high pressure milling technology such asmicrofluidizer or other rotor-stator type of mill or jet mill.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system suitable for commonly known sterilization technologiessuch as gamma irradiation, electron beam irradiation and autoclavesterilization.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system that can be manufactured using aseptic technique.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system suitable for gamma radiation sterilization.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration comprising a compound of formula (I) and asurfactant system suitable for sterilization technologies by electronbeam irradiation or autoclave sterilization.

An embodiment of the present invention is a pharmaceutical compositionfor parenteral administration that can be presented as a “ready to use”sterile suspension or lyophile for reconstitution.

In general, the pharmaceutical compositions of the present inventioncomprise 0.1-50% by weight of a compound of formula (I). In general, thepharmaceutical compositions of the present invention comprise 0.1-5%polysorbate 20 as a surfactant and 0.1-5% polyethylene glycol. Thepharmaceutical compositions of the present invention may comprise0.1-10% polysorbate 20 as a surfactant and 0.1-10% polyethylene glycol.

The compositions of the present invention may be administered bysubcutaneous or intramuscular injection. The compositions of the presentinvention may be administered by intradermal or intravitreal injectionor implant. The compositions of the present invention may beadministered by other parenteral routes of administration.

The preparation of the compositions of the present invention may beperformed by milling using a wet bead mill and sterilized by gammairradiation.

Another feature of the present invention is to simplify treatmentregimens for HIV with the goal of enhancing patient compliance byproviding a simplified dosage form containing therapeutically effectiveamounts of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

The present invention also features a method for treating HIV infectionsin a human, which method comprises administering to said human acomposition according to the invention. The present invention featuresthe use of a pharmaceutical composition according to the invention inthe treatment of HIV infections. The present invention features themanufacture of a medicament according to the invention for use inmedical therapy.

The present invention also features a method for treating HIV infectionsin a human which method comprises administering to said human acomposition according to the invention before, during, or after therapywith a compound of formula (I) in tablet or solution form.

It will be appreciated by those skilled in the art that reference hereinto “treatment” extends to treatment of an established malady, infectionor symptoms thereof.

The present invention also features a method for preventing HIVinfections in a human, which method comprises administering to saidhuman a composition according to the invention. The present inventionfeatures the use of a pharmaceutical composition according to theinvention in the prevention of HIV infections. The present inventionfeatures the manufacture of a medicament according to the invention foruse in prophylactic medical therapy.

The present invention also features a method for treating or preventingHIV infections in a human which method comprises administering to saidhuman a composition according to the invention before, during, or aftertherapy with a compound of formula (I) in tablet or solution form.

Methods for the preparation of a compound of formula (I) are describedin WO 2006/116764, WO2010/011814, WO2010/068262, and WO2010/068253incorporated herein by reference.

The pharmaceutical compositions of the invention are presented aspharmaceutical compositions suitable for parenteral administration. Thecompositions may also include a safe and effective amount of otheractive ingredients, such as antimicrobial agents, antiviral agents, orpreservatives.

It will be appreciated by those skilled in the art that the amount ofactive ingredients required for use in treatment will vary according toa variety of factors, including the nature of the condition beingtreated and the age and condition of the patient, and will ultimately beat the discretion of the attending physician, veterinarian or healthcare practitioner.

Compositions of the present invention enable patients greater freedomfrom multiple dosage regimens and ease the needed diligence required inremembering complex daily dosing times and schedules. The compositionsof the present invention are particularly suitable for administration asa single dose monthly, bi-monthly or tri-monthly, or at any intervalbetween 30 and 365 days, including every six or twelve months

Advantageously, the compositions of the present invention may beadministered once per month.

The compositions of the present invention conveniently allowadministration in unit dosage form containing, for example, from about 1mg to about 800 mg, 100 mg to about 800 mg of a compound of formula (I),from about 100 mg to about 600 mg or from about 100 mg to about 400 mgper unit dosage form.

The compositions of the present invention may be used in combinationwith other pharmaceutical formulations as a component of a multiple drugtreatment regimen.

Compositions of the present invention may also be packaged as articlesof manufacture comprising a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof;and therapeutically effective amount of one or more of the following:nucleoside reverse transcriptase inhibitor, non-nucleoside reversetranscriptase inhibitor, protease inhibitor, integrase inhibitor. Anexample of a non-nucleoside reverse transcriptase inhibitor isrilpivirine hydrochloride (TMC-278).

The packaging material may also have labelling and information relatedto the pharmaceutical composition printed thereon. Additionally, anarticle of manufacture may contain a brochure, report, notice, pamphlet,or leaflet containing product information. This form of pharmaceuticalinformation is referred to in the pharmaceutical industry as a “packageinsert.” A package insert may be attached to or included with apharmaceutical article of manufacture. The package insert and anyarticle of manufacture labelling provides information relating to thepharmaceutical composition. The information and labelling providesvarious forms of information utilized by health-care professionals andpatients, describing the composition, its dosage and various otherparameters required by regulatory agencies such as the United StatesFood and Drug Agencies.

The present invention further provides the following embodiments:

-   -   (a) A parenteral pharmaceutical composition comprising an        effective amount of compound of formula (I) or a        pharmaceutically acceptable salt thereof, for the long term        treatment of HIV infection, or prevention of HIV infection in an        individual at risk of being infected by HIV, wherein the        composition is administered intermittently at a time interval of        at least one week.    -   (b) The composition according to (a) wherein the composition is        administered once every two weeks.    -   (c) The composition according to (a) wherein the composition is        administered once every month.    -   (d) The composition according to any one of (a) to (c) wherein        the effective amount of compound of formula (I) or a        pharmaceutically acceptable salt thereof is selected such that        the blood plasma concentration of compound of formula (I) in a        subject is kept during a prolonged period of time at a level        between a maximum blood plasma level which is the blood plasma        level that causes significant side effects and the minimum blood        plasma level that is the lowest blood plasma level that causes a        compound of formula (I) to provide effective treatment or        prevention of HIV infection.    -   (e) The composition according to (d) wherein the blood plasma        level of a subject is kept at a level equal to or above about        150 ng/ml, in particular equal to or above about 600 ng/ml.    -   (f) The composition according to any one of (a) to (e), wherein        the composition is administered subcutaneously or        intramuscularly.    -   (g) The composition according to any one of (a) to (f), which        comprises the aforementioned surfactant system comprising        polysorbate and/or polyethylene glycol.    -   (h) A method for the treatment or prevention of an HIV infection        in a human comprising a pharmaceutical composition according to        any of the above (a) to (g).

The dose of a compound of formula (I) administered, which is the amountof compound (I) in the parenteral composition for use in the invention,may be selected such that the blood plasma concentration of compound (I)in a subject is kept during a prolonged period of time above a minimumblood plasma level. The term “minimum blood plasma level” (or C_(min.))in this context refers to the lowest efficacious blood plasma level,that is, the blood plasma level of compound (I) that provides effectiveprevention or treatment HIV infection. In the case of transmission ofHIV from an individual infected by HIV to an individual not infected byHIV, this is the lowest blood plasma level that is effective ininhibiting said transmission.

The blood plasma level of compound (I) in a subject may be kept at alevel above a minimum blood plasma level of about 170 ng/ml, about 700ng/ml, or about 1000 ng/ml. The blood plasma levels of compound (I) in asubject may be kept above these minimum blood plasma levels because atlower levels the drug may no longer be effective, thereby increasing therisk of transmission of HIV infection, and may be suboptimal fortreatment of HIV infected subjects. Plasma levels of compound (I) may bekept at higher levels to avoid the development of HIV mutations, whilemaintaining a safety margin.

An advantage of the mode of administration of compound (I) is that highC_(min) levels can be achieved without a commensurate high C_(max),which could mitigate potential side effects associated with C_(max).

The effective amount of compound (I) to be administered may be selectedsuch that the blood plasma concentrations in a subject are kept during aprolonged period of time at a level between a maximum plasma level (orC_(max)) and the minimum blood plasma level (or C_(min)).

In some embodiments the blood plasma level of compound (I) in a subjectmay be kept between the minimum blood plasma level (or C_(min) asspecified above) and the lower maximum plasma level of compound (I) (orC_(max)) which is defined as the level that corresponds to the lowestblood plasma level where compound (I) acts therapeutically. The lowestlevel where compound (I) acts therapeutically is the lowest blood plasmalevel that is effective in inhibiting replication of HIV in individualsinfected by HIV so that the viral load of HIV is relatively low, forexample where the viral load (represented as the number of copies ofviral RNA in a specified volume of serum) is below about 200 copies/ml,in particular below about 100 copies/ml, more particularly below 50copies/ml, specifically below the detection limit of the assay for HIV.

As mentioned above, the blood plasma levels of compound (I) depend onthe amount of active ingredient in each parenteral dosage administered.However, it also depends on the frequency of the administrations (i.e.the time interval between each administration). Both parameters can beused to direct the blood plasma levels to the desired values. The dosemay be higher where administrations are less frequent.

Although the plasma levels of compound (I) should remain below a maximumor above a minimum value, they may surpass the maximal value or dropbelow the minimal value during relatively short periods of time, whichmay be as short as possible. The maximum and minimum plasma levelstherefore can be expressed as mean plasma levels during a certain periodof time.

In some instances there may be a small initial plasma concentration peakshortly after administration, after which the plasma levels achieve asteady-state.

The dose to be administered may be calculated on a basis of about 1mg/day to about 50 mg/day, preferably 3 mg/day to about 30 mg/day. Thiscorresponds to a weekly dose of about 7 mg to about 350 mg, preferablyabout 20 mg to about 200 mg, or to a monthly dose of about 30 mg toabout 1500 mg, preferably about 90 mg to about 900 mg. Doses for otherdosing regimens can readily be calculated by multiplying the daily dosewith the number of days between each administration.

The dose to be administered may be calculated on a basis of about 0.001mg/kg/day to about 1 mg/kg/day, preferably 0.05 mg/kg/day to about 0.5mg/kg/day. This corresponds to a weekly dose of about 0.5 mg to about500 mg, preferably about 20 mg to about 200 mg, or to a monthly dose ofabout 30 mg to about 1500 mg, preferably about 90 mg to about 900 mg.Doses for other dosing regimens can readily be calculated by multiplyingthe daily dose with the number of days between each administration.

Once administered, the blood plasma levels of compound (I) in a subjectmay be more or less stable. After initial rise of the blood plasmalevels, a steady state mode may be achieved during a prolonged period oftime. By “steady state” is meant the condition in which the amount ofdrug present in the blood plasma of a subject stays at more or less thesame level over a prolonged period of time. The plasma levels ofcompound (I) may then gradually decrease over time, and when the minimumplasma level is reached, then the next dose of compound (I) may beadministered. The term “stays at more or less the same level” does notexclude that there can be small fluctuations of the plasmaconcentrations within an acceptable range, for example, within about30%, about 20%, or about 10%.

The parenteral compositions of compound (I) may be administered byintravenous injection or, preferably by subcutaneous or intramuscularadministration.

The present invention is based on the use of parenteral compositions ofthe active ingredient compound (I) and therefore the nature of thecarrier is selected for suitability for parenteral administration. Thecarrier in most cases will comprise sterile water, in although otheringredients, for example, to aid solubility, may be included. Injectablesolutions or suspensions, for example, may be prepared in which thecarrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Further, the carrier may contain thesurfactant system mentioned above such as polysorbate andpolyethyleneglycol.

EFFECT OF THE INVENTION

The parenteral pharmaceutical composition comprising compound (I) of thepresent invention is long-acting. Accordingly, the composition is usefulfor the treatment or prevention of HIV infection with administration atlong time intervals, compared with conventional compositions or withother compounds similar to compound (I) in chemical structure. Thecompositions of the present invention can be intermittently administeredto a patient, e.g., once per week, once per month, once per every 2months, or one per every 3 months. Therefore, the compositions of thepresent invention and an administration by subcutaneous (SC) orintramuscular (IM) injection using the same can lead to a remarkablereduction in medication (pill) burden or difficulty in patientcompliance. Further, such intermittent administration of a compositionof the present invention can contribute to maintaining therapy atappropriate compliance which leads to prevention of emergence of drugresistant HIV and maintaining the efficacy of therapy for an extendedperiod of time.

EXAMPLES

The following examples further describe and demonstrate particularembodiments within the scope of the present Invention. The examples aregiven solely for illustration and are not to be construed as limitationsas many variations are possible without departing from spirit and scopeof the Invention.

Example 1 Pharmaceutical Composition

TABLE 1 Composition of a compound of formula (I) Injectable SuspensionQuantity Component (mg/mL) Function Compound of Formula (I) 200.0 ActiveMannitol 45.0 Tonicity agent Polysorbate 20 20.0 Wetting agentPolyethylene Glycol (PEG) 3350 20.0 Stabilizer Water for Injection QS to1.0 mL Solvent

Manufacturing Process

A compound of formula (I), mannitol, polysorbate 20, PEG 3350, and waterfor injection were compounded and milled using a wet bead mill. Theresulting suspension was filled into 3 mL, USP Type I glass vials at afill volume of 1.5 mL, the vials are stoppered and sealed, and thenterminally sterilized by gamma irradiation.

Example 2 Particle Size

A sample of a compound of formula (I) injectable suspension prepared bythe process as described in Example 1 was irradiated by gammairradiation at 29.9-31.5 kGy dose. The milling time was 5 hours. Theparticle size determined by laser diffraction technique is thefollowing:

×10=75 nm

×50=157 nm

×90=646 nm

×50 of less than 200 nm was achieved.

Example 3 Gamma Irradiation

A sample of a compound of formula (I) injectable suspension prepared bythe process as described in Example 1 was irradiated by gammairradiation at 29.9-31.5 kGy dose. Samples pre gamma irradiation andpost gamma irradiation were tested for drug related impurities by HPLC.

Total Drug Related Impurities, % area/area Pre Gamma Irradiation 0.19Post Gamma Irradiation 0.16

The formulation is stable upon gamma irradiation.

Example 4 Manufacturing Process Using High Pressure Microfluidizer

TABLE 2 Composition of a compound of formula (I) Injectable SuspensionQuantity Component (mg/mL) Function Compound of Formula (I) 200.0 ActiveMannitol 45.0 Tonicity agent Polysorbate 20 20.0 Wetting agentPolyethylene Glycol (PEG) 3350 20.0 Stabilizer Water for Injection QS to1.0 mL Solvent

Manufacturing Process

A compound of formula (I), mannitol, polysorbate 20, PEG 3350, and waterfor injection were compounded and microfluidized using a MicrofluidizerM-110P. The suspension was passed through an interaction chamber (G10Z)with a minimum internal dimension of 87 μm and after 50 pass achievedthe particle size as listed below:

×10=82 nm

×50=221 nm

×90=726 nm

Example 5 Rat Pharmacokinetics

A compound of formula (I) was given once to male and female rats(10/sex/group) at 0 (vehicle), 5, 30, or 100 mg/kg by subcutaneous (SC)injection or 0 (vehicle), 2.5, 10, or 75 mg/kg by intramuscular (IM)injection. After dosing, rats were retained for a 75- to 76-day (SC,including 1^(st) 5 control rat/sex) or 84- to 85-day (IM, last 5 controlrats/sex; IM) nontreatment period. The vehicle control rats were givenboth SC and IM injections. FIGS. 1-4 display present plasmaconcentration-time profiles by route of administration and gender.

1. A parenteral pharmaceutical composition comprising a compound offormula (I)

or a pharmaceutically acceptable salt thereof, and a surfactant systemcomprising a polysorbate and polyethylene glycol.
 2. A pharmaceuticalcomposition according to claim 1 for subcutaneous administration.
 3. Apharmaceutical composition according to claim 1 for intramuscularadministration.
 4. A pharmaceutical composition according to claim 1 foronce per month administration.
 5. A pharmaceutical composition accordingto claim 1 for administration once every two months.
 6. A pharmaceuticalcomposition according to claim 1 for administration once every threemonths.
 7. A pharmaceutical composition according to claim 1 foradministration at any interval between 30 and 365 days.
 8. Apharmaceutical composition according to claim 1 wherein the amount of acompound of formula (I) is from about 10 mg to about 500 mg per ml ofthe dosage form.
 9. A pharmaceutical composition according to claim 1wherein the particle size is less than or equal to 200 nm.
 10. Apharmaceutical composition according to claim 1 wherein the particlesize is in the range of 0.1-0.5 μm.
 11. A pharmaceutical compositionaccording to claim 1 that can be terminally sterilized by gammairradiation.
 12. A method for the treatment of an HIV infection in ahuman comprising administering a pharmaceutical composition according toclaim
 1. 13. A method for the prevention of an HIV infection in a humancomprising administering a pharmaceutical composition according toclaim
 1. 14. (canceled)
 15. (canceled)
 16. A pharmaceutical compositionaccording to claim 1 comprising 0.1-10% polysorbate 20 and 0.1-10%polyethylene glycol.
 17. A parenteral pharmaceutical composition foradministration once every one to three months, comprising 0.1-50% byweight of a compound of formula (I)

0.1-10% polysorbate 20, and 0.1-10% polyethylene glycol, and wherein themean particle size of said composition is 0.1-1.0 μm.
 18. Apharmaceutical composition according to claim 17 wherein the particlesize is 200 nm.
 19. A pharmaceutical composition according to claim 17for subcutaneous or intramuscular administration.
 20. A method for thetreatment of an HIV infection in a human comprising administering apharmaceutical composition according to claim
 17. 21. A method for theprevention of an HIV infection in a human comprising administering apharmaceutical composition according to claim
 17. 22. A combination of aparenteral pharmaceutical composition for administration once every 1 to3 months comprising a compound of formula (I)

and rilpivirine hydrochloride.